© 2005 American Thoracic Society
Potential Mechanisms for Mortality Reduction Associated with Combination Antibiotic Therapy among Severely Ill Patients with Pneumococcal BacteremiaTo the Editor:Baddour and colleagues' prospective study design and large numbers of subjects help to confirm that treatment of bacteremic pneumococcal pneumonia with two drugs is associated with improved survival as compared with single drug therapy (1). Previous studies showed similar results (2–4). The consistency of these findings suggests that the association between combination therapy and improved survival is causal. However, the mechanism(s) by which such benefit is derived is unknown. Baddour and colleagues help to clarify this issue by confirming that this survival benefit is not dependent on inclusion of a macrolide in combination regimens (3), and by showing that the reduction in mortality occurred exclusively among the 94 critically ill patients (14-d mortality rates of 23.4% and 55.3% among critically ill recipients of two- and one-drug therapy, respectively, p = 0.0015), with no discernible difference in mortality among the 498 patients who were less ill (1). Thus, it seems that either a second antibiotic, irrespective of the agent used, confers added survival benefit only with critical illness, or single-drug therapy somehow becomes less effective in that context. There is conflicting evidence in favor of the former, "value-added" hypothesis. After assigning each of the 201 patients in their retrospective series a predicted risk of mortality based on APACHE II scores, Waterer and coworkers (3) found that the observed mortality among single-antibiotic recipients was similar to the predicted mortality, whereas the observed mortality for two-drug recipients was nearly 10% lower than predicted (6.9% and 16.4%, respectively), suggesting that the addition of a second drug was responsible for the differences in mortality. By contrast, the high mortality rate of the critically ill recipients of one-drug therapy reported by Baddour and colleagues (26 [55.3%] of 47) (1) seems more consistent with a loss of effectiveness of single-drug therapy in this setting.
Altered antibiotic pharmacokinetics during critical illness may explain why an otherwise effective single-drug regimen might fail in critical illness. Reductions in serum proteins, especially albumin, and an expanded volume of distribution may hasten drug clearance so long as excretory—renal and/or hepatic—function remains intact (5). This has been shown to occur with ceftriaxone, a third-generation cephalosporin commonly used to treat community-acquired pneumonia, whose prolonged elimination half-life in normal subjects—approximately 8 h—depends upon extensive protein binding. Joynt and colleagues (6) found that free ceftriaxone levels fell to undetectable levels within 8 h of dosing in all eight critically ill adults with normal renal function given ceftriaxone 2 g daily. Since the unbound moiety of ceftriaxone and other protein-bound antibiotics is presumed to be responsible for bacterial killing, and because, as with other Ceftriaxone was likely to have been given to many single-antibiotic recipients in the studies showing improved survival for combination therapy in bacteremic pneumococcal pneumonia: 25 (53%) of 47 reported by Baddour and colleagues (1), 25 (25%) of 99 described by Waterer and colleagues (3), and 106 (62%) of 171 reported by Martinez and colleagues (4) received unspecified third-generation cephalosporins. Did the specific antibiotic type correlate with survival in these studies, especially after stratifying for the presence of critical illness as performed by Baddour and colleagues (1)? Highly variable and often inadequate pharmacokinetic parameters have been described for antibiotics other than ceftriaxone in critical illness (8, 9). Thus, dosing antibiotics to better account for such variations may be necessary to reap their full benefits in the intensive care unit (10).
Stroger Hospital of Cook County, Chicago, Illinois FOOTNOTES Conflict of Interest Statement: D.N.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. REFERENCES
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-lactam antibiotics, free ceftriaxone levels must exceed the minimum inhibitory concentration of the infecting pathogen for at least 40% of the dosing interval—9.6 h when dosed every 24 h—to cure bacterial infections reliably, clinical failure is predictable under these circumstances (